Preparation of orlistat and orlistat crystalline forms

ABSTRACT

The present invention is directed to a process of converting lipstatin to orlistat by catalytic hydrogenation. The present invention further discloses novel crystalline solid orlistat forms, designated form I and form II and methods for their preparation.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. § 1.119(e) ofProvisional Application Serial No. 60/337,218 filed Dec. 4, 2001, thedisclosure of which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

[0002] The present invention relates to a method of converting lipstatinto orlistat. The present invention also relates to crystalline solidorlistat (e.g., form I and form II).

BACKGROUND OF THE INVENTION

[0003] Orlistat is currently available for the treatment of obesity. Ithas the chemical name (2S, 3S,5S)-5-[(S)-2-formamido-4-methylvaleryloxy]-2-hexy-3-hydroxyhexadecanoicacid lactone [a/k/a “N-formyl-L-leucine ester with (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone”,(−)-tetrahydrolipstatin, tetrahydrolipstatin, and orlipastat] and itschemical formula is:

[0004] Orlistat has been purified from a fermentation broth ofStreptomyces toxytricini (See U.S. Pat. No. 4,598,089 and Eur. Pat.Appl. 129,748). U.S. Pat. No. 4,598,089 is directed to orlistat and itsuse in treating obesity. The cultivation, fermentation and purificationof orlistat produced in Streptomyces toxytricini were disclosed. Theprocess involves purifying orlistat using a silica gel chromatography.The desired orlistat may then be subjected to further purification witha reverse-phase chromatography; thus, multiple chromatographies arerequired. The repeated purification processes is costly and impracticalfor large scale manufacturing.

[0005] U.S. Pat. No. 4,983,746 relates to a process for the artificialsynthesis of orlistat which involves producing oxetanone derivatives;and esterification of the acid derivatives with an alcohol. Thedisadvantage of artificially synthesizing orlistat is its high cost,especially with industrial scale production.

[0006] EP 638317 describes a pharmaceutical composition includingorlistat. However, there is no disclosure regarding the production andpurification of orlistat. Such obtained orlistat is not desirable forpreparing a pharmaceutical composition as it requires high purity.

[0007] There is a continuous need to improve the preparation oforlistat.

[0008] The present invention also relates to the solid state physicalproperties of orlistat. These properties can be influenced bycontrolling the conditions under which orlistat is obtained in solidform. Solid state physical properties include, for example, theflowability of the milled solid. Flowability affects the ease with whichthe material is handled during processing into a pharmaceutical product.When particles of the powdered compound do not flow past each othereasily, a formulation specialist must take that fact into account indeveloping a tablet or capsule formulation, which may necessitate theuse of glidants such as colloidal silicon dioxide, talc, starch ortribasic calcium phosphate.

[0009] Another important solid state property of a pharmaceuticalcompound is its rate of dissolution in aqueous fluid. The rate ofdissolution of an active ingredient in a patient's stomach fluid canhave therapeutic consequences since it imposes an upper limit on therate at which an orally-administered active ingredient can reach thepatient's bloodstream. The rate of dissolution is also a considerationin formulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

[0010] These practical physical characteristics are determined by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. A particularcrystalline form may also give rise to distinct spectroscopic propertiesthat may be detectable by powder X-ray crystallography, or otherparameters including solid state ¹³C NMR spectrometry and infraredspectrometry. The polymorphic form may also give rise to thermalbehavior different from that of the amorphous material or anothercrystalline form. Thermal behavior is measured in the laboratory by suchtechniques as capillary melting point, thermogravimetric analysis (TGA)and differential scanning calorimetry (DSC) and can be used todistinguish some polymorphic forms from others.

SUMMARY OF THE INVENTION

[0011] The present invention provides a process of preparing orlistat,comprising the steps of hydrogenating lipstatin in an organic solvent inthe presence of a catalyst to obtain orlistat. Preferably, the organicsolvent is selected from the group consisting of acetonitrile, alcohol,and acetone. Most preferably, the organic solvents are methanol andacetone.

[0012] Preferably, the catalyst is selected from the group consisting ofpalladium and nickel. Preferably, the hydrogenating step is performed ata temperature between about 10° C. to about 50° C. Preferably, thehydrogenating step is performed at reaction pressure of less than 5 bar.More preferably, the hydrogenating step is performed at reactionpressure between about 1 to about 3 bar. Most preferably, thehydrogenating step is performed at reaction pressure of about 1 bar.

[0013] The present invention provides a crystalline solid orlistat, orhydrate or solvate thereof, characterized by data selected from thegroup consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and22.3±0.2 degrees two-theta and a DSC melting endotherm at about 46.7° C.

[0014] Preferably, the crystalline solid orlistat is characterized by aXRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degreestwo-theta.

[0015] Preferably, the crystalline solid orlistat is furthercharacterized by a XRD pattern substantially as depicted in FIG. 1.

[0016] Preferably, the crystalline solid orlistat characterized by a DSCmelting endotherm at about 46.7° C.

[0017] The present invention provides a crystalline solid orlistat, orhydrate or solvate thereof, characterized by data selected from thegroup consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3,19.2 and 22.0±0.2 degrees two-theta, and a DSC melting endotherm atabout 46.6° C.

[0018] Preferably, the crystalline solid orlistat is characterized by aXRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2degrees two-theta.

[0019] Preferably, the crystalline solid orlistat is furthercharacterized by a XRD pattern substantially as depicted in FIG. 2.

[0020] Preferably, the crystalline solid orlistat is characterized by aDSC melting endotherm at about 46.6° C.

[0021] The present invention provides a process of preparing crystallinesolid orlistat, or hydrate or solvate thereof, characterized by dataselected from the group consisting of a XRD pattern with peaks at 5.8,18.5, 19.5 and 22.3±0.2 degrees two-theta and a DSC melting endotherm atabout 46.7° C., comprising the steps of:

[0022] (a) dissolving orlistat in a solvent;

[0023] (b) adding an anti-solvent or water to the solvent; and

[0024] (c) isolating the crystalline solid orlistat.

[0025] Preferably, the solvent is a lower alkyl alcohol, acetone,acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutylketone, and hexane.

[0026] Preferably, the lower alkyl alcohol is selected from the groupconsisting of methanol, ethanol, n-propanol, and isopropanol.Preferably, the anti-solvent is a hydrocarbon. More preferably, thehydrocarbon is selected from the group consisting of hexane, cyclohexaneand heptane. Most preferably, the solvent is methanol and theanti-solvent is hexane. Preferably, the steps (a) to (c) are repeated atleast once to increase the purity of the crystalline solid orlistat.

[0027] The present invention provides the crystalline solid orlistatprepared in accordance with the process comprising the steps of:

[0028] (a) dissolving orlistat in a solvent;

[0029] (b) adding an anti-solvent or water to the solvent; and

[0030] (c) isolating the crystalline solid orlistat.

[0031] The present invention provides a process for preparing acrystalline solid orlistat, or hydrate or solvate thereof, characterizedby data selected from the group consisting of a XRD pattern with peaksat 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSCmelting endotherm at about 46.6° C., comprising the steps of:

[0032] (a) mixing orlistat in hexane to form a mixture at a firsttemperature;

[0033] (b) lowering the first temperature of the mixture sufficiently toprecipitate; and

[0034] (c) isolating crystalline solid orlistat.

[0035] Preferably, steps (a) to (c) are repeated at least once toincrease the purity of the crystalline solid orlistat.

[0036] The present invention provides the crystalline solid orlistatprepared in accordance with the process comprising the steps of:

[0037] (a) mixing orlistat in hexane to form a mixture at a firsttemperature;

[0038] (b) lowering the first temperature of the mixture sufficiently toprecipitate; and

[0039] (c) isolating crystalline solid orlistat.

[0040] The present invention provides a process of preparing a mixtureof crystalline solid orlistat, or hydrate or solvate thereof,characterized by data selected from the group consisting of a XRDpattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta, aDSC melting endotherm at about 46.7° C., a XRD pattern with peaks at4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSCmelting endotherm at about 46.6° C., comprising the steps of:

[0041] (a) dissolving orlistat in a solvent; and

[0042] (b) inducing crystallization to obtain the mixture of crystallinesolid orlistat.

[0043] Preferably, the solvent is at least one alcohol selected from thegroup consisting of methanol, ethanol, n-propanol, 1-propanol,2-propanol, isopropanol, 1-butanol, i-butanol, sec-butanol,tert-butanol, N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile,acetone, ethyl acetate, isobutyl acetate, methyl isobutyl ketone, andacetic acid. Preferably, the solvent is an aliphatic hydrocarbon. Morepreferably, the aliphatic hydrocarbon is selected from the groupconsisting of hexane, pentane and heptane. Preferably, the solventcontains water. More preferably, the solvent is methanol. Mostpreferably, the mixture of methanol and water is present in a v/v ratioof about 1:0.3. Preferably, the solvent is a mixture of a first alcoholin combination with a second alcohol selected from the group consistingof methanol, ethanol, isopropanol, propanol, butanol, sec-butanol andt-butanol. Preferably, the crystallization step is induced by adding ananti-solvent or cooling.

[0044] The present invention provides the crystalline solid orlistathaving a purity of at least about 95%. More preferably, the crystallinesolid orlistat has a purity of at least about 98%.

[0045] The present invention provides a process of preparing orlistat,comprising the steps of:

[0046] a) preparing fermentation broth containing lipstatin;

[0047] b) extracting lipstatin from the fermentation broth;

[0048] c) hydrogenating the lipstatin to obtain orlistat; and

[0049] d) separating the orlistat.

[0050] Preferably, the hydrogenating step a) is carried out in anorganic solvent in the presence of a catalyst to obtain orlistat.

BRIEF DESCRIPTION OF THE DRAWING

[0051]FIG. 1 represents the XRD diffractogram of crystalline solidorlistat form I.

[0052]FIG. 2 represents the XRD diffractogram of crystalline solidorlistat form II.

DETAILED DESCRIPTION OF THE INVENTION

[0053] Definitions:

[0054] As used herein, the term “lipstatin” refers to a precursor oforlistat. Orlistat, also known as tetrahydrolipstatin, has four morehydrogens than lipstatin.

[0055] As used herein, the term “under reduced pressure” refers topressure which is less than 760 mm Hg. The term “vacuum” refers topressure close to 0 mm Hg.

[0056] As used herein, the term “hydrogenation” refers to the catalyticaddition of hydrogen to lipstatin with hydrogen gas in the presence of acatalyst; such catalyst includes palladium (Pd) or nickel (Ni).

[0057] As used herein, the term “XRD” refers to X-ray powderdiffraction. One of skill in the art would appreciate that orlistatcrystalline forms I or II possess unique XRD peaks provided herein.

[0058] As used herein, the term “bar” refers to 760 mm Hg. For example 1bar refers to 760 mmHg and 2 bars refers to 2×760 mmHg.

[0059] The analysis of the samples was performed by HPLC, using RC C 18type, 5 micron column. The mobile phase was a mixture of acetonitrileand 0.1% phosphoric acid in a vol/vol ratio of 8 to 2. Detection wasdone by UV detector at 205 nm wavelength.

[0060] Crystalline Solid Orlistat Form I

[0061] The present invention provides a crystalline solid orlistat, orhydrate or solvate thereof, characterized by data selected from thegroup consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and22.3±0.2 degrees two-theta and a DSC melting endotherm at about 46.7° C.Preferably, the crystalline solid orlistat is characterized by a XRDpattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta.

[0062] Preferably, the crystalline solid orlistat is characterized by aXRD pattern substantially as depicted in FIG. 1.

[0063] Preferably, the crystalline solid orlistat characterized by a DSCmelting endotherm at about 46.7° C.

[0064] Orlistat Crystalline Form II

[0065] The present invention provides a crystalline solid orlistat, orhydrate or solvate thereof, characterized by data selected from thegroup consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3,19.2 and 22.0±0.2 degrees two-theta, a DSC melting endotherm at about46.6° C.

[0066] Preferably, the crystalline solid orlistat is characterized by aXRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2degrees two-theta.

[0067] Preferably, the crystalline solid orlistat is characterized by aXRD pattern substantially as depicted in FIG. 2.

[0068] Preferably, the crystalline solid orlistat is characterized by aDSC melting endotherm at about 46.6° C.

[0069] According to another embodiment, the present invention provides aprocess of preparing crystalline solid orlistat, or hydrate or solvatethereof, characterized by data selected from the group consisting of aXRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-thetaand a DSC melting endotherm at about 46.7° C., comprising the steps of:

[0070] (a) dissolving orlistat in a solvent;

[0071] (b) adding an anti-solvent or water to the solvent; and

[0072] (c) isolating the crystalline solid orlistat.

[0073] Preferably, the solvent is a lower alkyl alcohol, acetone,acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutylketone, and hexane. Preferably, the lower alkyl alcohol is selected fromthe group consisting of methanol, ethanol, n-propanol, and isopropanol.

[0074] Preferably, the anti-solvent is selected from the groupconsisting of hydrocarbon. More preferably, the hydrocarbon is selectedfrom the group consisting of heptane, hexane, and cyclohexane. Mostpreferably, the solvent is methanol and the anti-solvent is hexane.

[0075] Preferably, the process steps of preparing a crystalline solidorlistat is repeated.

[0076] According to another embodiment, the present invention provides aprocess for preparing a crystalline solid form, or hydrate or solvatethereof, characterized by data selected from the group consisting of aXRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2degrees two-theta, a DSC melting endotherm at about 46.6° C., comprisingthe steps of:

[0077] (a) mixing orlistat in hexane to form a mixture at a firsttemperature;

[0078] (b) lowering the first temperature of the mixture sufficiently toprecipitate; and

[0079] (c) isolating crystalline solid orlistat.

[0080] According to another embodiment, the present invention furtherprovides a process of preparing a mixture of crystalline solid orlistatforms, or hydrate or solvate thereof, characterized by data selectedfrom the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5and 22.3±0.2 degrees two-theta, a DSC melting endotherm at about 46.7°C., a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2degrees two-theta, and a DSC melting endotherm at about 46.6° C.,comprising the steps of:

[0081] (a) dissolving orlistat in a solvent; and

[0082] (b) inducing crystallization to obtain the mixture of crystallinesolid orlistat.

[0083] Preferably, the solvent is selected from the group consisting ofmethanol, ethanol, n-propanol, 1-propanol, 2-propanol, isopropanol,1-butanol, i-butanol, sec-butanol, tert-butanol, N,N-dimethyl formamide,dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, isobutylacetate, methyl isobutyl ketone, and acetic acid. Preferably, thesolvent is an aliphatic hydrocarbon. More preferably, the aliphatichydrocarbon is selected from the group consisting of hexane, pentane andheptane.

[0084] Preferably, the solvent contains water. Preferably, the solventis methanol. More preferably, the mixture of methanol and water ispresent in a v/v ratio of about 1:0.3.

[0085] Preferably, the solvent is a mixture of an alcohol in combinationwith another solvent selected from the group consisting of methanol,ethanol, isopropanol, propanol, butanol, sec-butanol and t-butanol.

[0086] Preferably, the crystallization step is induced by adding ananti-solvent or by cooling.

[0087] According to another embodiment, the present invention providescrystallized orlistat has a purity of at least about 95%. Morepreferably, the crystallized orlistat has a purity of at least about98%.

[0088] According to another embodiment, the present invention provides aprocess for preparing novel crystalline forms of orlistat bycrystallization. A preferred embodiment includes crystallization using acrystallization solution which is a mixture of a solvent and water.Preferably, the solvent comprises of methanol, ethanol, 1-propanol,2-propanol, 1-butanol, i-butanol, tert-butanol, N,N-dimethyl formamide,dimethyl sulfoxide, acetonitrile, acetone or acetic acid. Preferably, acrystallization solution is a mixture of methanol and water in avolume-to-volume ratio of 1 mL (methanol) to 0.3 mL (water).

[0089] One of skill in the art would appreciate that some conditions forcrystallization can be modified without affecting crystalline form ofthe orlistat obtained. For example, warming of the mixture may benecessary to completely dissolve the starting material. If warming doesnot clarify the mixture, the mixture can be diluted or filtered. Tofilter, the hot mixture can be passed through paper, glass fiber orother membrane material, or a clarifying agent such as celite. Dependingupon the equipment used and the concentration and temperature of thesolution, the filtration apparatus may need to be preheated to avoidpremature crystallization.

[0090] The conditions can also be changed to induce precipitation. Apreferred way of inducing precipitation is to reduce the solubility ofthe solute, for example, by cooling the solvent.

[0091] Alternatively, an anti-solvent may be added to a solution todecrease solubility of a particular compound, thus resulting inprecipitation.

[0092] Another manner to accelerate crystallization is by seeding with acrystal of the product or scratching the inner surface of thecrystallization vessel with a glass rod. Other times, crystallizationcan occur spontaneously without any inducement. The present inventioncovers both embodiments where precipitation is induced/accelerated oroccurs spontaneously, except in the circumstance where theinducement/acceleration is critical for obtaining a particularcrystalline form, e.g., the process requires the use of a particularanti-solvent.

[0093] It is appreciated that the present crystallization process can berepeated several times. The repetition of crystallization process willimprove the purity of the crystalline orlistat. According to oneembodiment, the present invention provides a process for hydrogenatinglipstatin to obtain orlistat. Crude lipstatin can be used for thehydrogenation process to obtain orlistat. Other sources includingcommercially available sources of lipstatin can also be used.Preferably, crystalline lipstatin is used for the hydrogenation.

[0094] According to another embodiment, Pd (palladium) or Ni (nickel)catalysts can be used. Hydrogenation is performed at an reactionpressure not greater than 5 bar (i.e., 5 times atmospheric pressure (760mmHg)). The preferred reaction pressure is about 1-3 bar. The mostpreferred reaction pressure is about atmospheric pressure (760 mmHg).The preferred reaction temperature is about 10 to about 50° C. Thepreferred solvents are acetonitrile and alcohols. The most preferredsolvents are methanol and acetone.

[0095] The present invention is described in further detail withreference to the following examples. However, the scope of the presentinvention is by no means restricted by these specific examples.

EXAMPLES Example 1

[0096] A fermentation broth (3.4 kg) containing lipstatin was extractedwith i-butyl acetate at a pH of about 2.0-10.5. The extraction achieveda yield of 94%.

[0097] The i-butyl acetate phase was further washed with water at a pHof about 3.0-8.0.

[0098] The washed i-butyl acetate phase was concentrated in a vacuum ata maximum temperature of about 80° C. The concentrated i-butyl acetatephase(311.9 grams) contained the lipstatin (1.305 gram) and was thenextracted three times with methanol. The methanol phases were combined.The combined methanol phase contained 1.100 gram of lipstatin. Theoverall yield of the steps was 79%.

Example 2

[0099] A methanol phase was produced according to Example 1.

[0100] The methanol phase (936 mL) was concentrated under reducedpressure to an oily residue (20.39 grams). The oily residue was dilutedwith acetonitrile (125 mL). The diluted solution contained the lipstatin(1.100 gram).

[0101] The acetonitrile solution was extracted three times with hexane.The hexane phases were combined (300 mL) and washed three times withacetonitrile (10 mL). The acetonitrile phases were combined. Thecombined acetonitrile phases contained the lipstatin (952 mg). Thesolution was concentrated in vacuum at a maximum temperature of 60° C.The mass of concentrate was 4.95 grams. The yield of this step was 87%.

Example 3

[0102] An acetonitrile concentrate was produced according to Example 2.

[0103] The concentrate (4.95 grams) was diluted with a methanol:water(70:15) mixture (85 mL) resulting in a diluted solution containinglipstatin. The diluted solution containing lipstatin (952 mg) wasextracted five times with hexane (85 mL). The hexane phases werecombined and concentrated in vacuum at a maximum temperature of about60° C. to a volume of 85 mL.

[0104] The concentrated hexane solution was extracted five times withmethanol:water (70:15) mixture (85 mL). The combined methanol:waterphase was concentrated in vacuum at a maximum temperature of about 80°C. to an oily residue (1.267 gram). The oily residue contained lipstatin(748 mg). The yield of this step was 86%.

Example 4

[0105] An oily residue was produced according to Example 3.

[0106] The oily residue (603 mg) was diluted with methanol (10 mL). Thediluted solution contained lipstatin (356 mg) and was passed through ananion-exchanger (15 mL). The type of anion-exchanger used was Amberlite™IRA 67 resin in hydroxide form. The resin was washed with methanol.Fractions containing lipstatin were collected. The volume of thecombined fractions was 20 mL. The combined fractions contained about 302mg lipstatin and about 142 mg other substances.

Example 5

[0107] A lipstatin containing 302 mg active substance was producedaccording to Example 4.

[0108] The lipstatin was hydrogenated in the presence of a catalyst in amethanol solution. The hydrogenation of about 302 mg lipstatin resultedin about 270 mg orlistat (tetrahydrolipstatin).

[0109] The present invention of orlistat crystallization will now befurther explained in the following examples. These examples should notbe construed as limiting to the invention.

[0110] X-Ray Diffraction Method:

[0111] Conditions for obtaining powder x-ray diffraction (XRD) patterns:The powder x-ray diffraction patterns were obtained by methods known inthe art using a Philips x-ray powder diffractometer, Phillips GeneratorTW 1830; Goniometer PW 3020; MPD Control PW 3710; X-Ray tube with Cutarget anode; Monochromator proportional counter; Divergence slits 1⁰,Receiving slit 0.2 mm, Scatter slit 1⁰; 40 KV, 30 mA; and Scanning speedstep 0.05 degrees to 2 degrees/min.

Example 6

[0112] Orlistat (270 mg) was crystallized from methanol (1 mL) by addingwater (200 microlitres) after cooling at a temperature of about 0-10° C.for at least 10 hours. Crystals were filtered and dried. Crystallizationresulted in orlistat (160 mg). The purity was 80%. The purity oforlistat was increased to 95% and further 98% further crystallization.

Example 7

[0113] Orlistat (produced according to Examples 5 (160 mg)) wascrystallized from hexane (1.6 mL) after cooling at a temperature ofabout 0-10° C. for at least 10 hours. Crystals were filtered and dried.The crystallization resulted in orlistat (105.7 mg). The purity wasabout 89%. The purity of orlistat was increased to 95% and further 98%further crystallization.

Example 8

[0114] 0.7 gram orlistat was dissolved in 0.7 mL ethanol. Hexane of 0.7mL was added to the solution. It was dried at 20-25° C. for 24 hours. Itwas further dried at 38° C. for 48 hours without any filtration (samplenumber 1-1).

Example 9

[0115] 0.7 gram orlistat was dissolved in 1.0 mL acetonitrile. Water of0.3 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 2).

Example 10

[0116] 0.7 gram orlistat was dissolved in 0.7 mL acetonitrile. Hexane of0.7 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 2-1).

Example 11

[0117] 0.7 gram orlistat was dissolved in 0.7 mL n-Propanol. Hexane of0.7 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 3-1).

Example 12

[0118] 0.7 gram orlistat was dissolved in 1.0 mL isopropanol. Water of0.3 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dreid at 38° C. for 48 hours without anyfiltration (sample number 4).

Example 13

[0119] 0.7 gram orlistat was dissolved in 0.7 mL isopropanol. Hexane of0.7 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 4-1).

Example 14

[0120] 0.7 gram orlistat was dissolved in 1.0 mL acetone. Water of 0.3mL was added to the solution. It was dried at 20-25° C. for 24 hours. Itwas further fried at 38° C. for 48 hours without any filtration (samplenumber 5).

Example 15

[0121] 0.7 gram orlistat was dissolved in 0.7 mL acetone. Hexane of 0.7mL was added to the solution. It was dried at 20-25° C. for 24 hours. Itwas further dried at 38° C. for 48 hours without any filtration (samplenumber 5-1).

Example 16

[0122] 0.7 gram orlistat was dissolved in 0.7 mL ethyl acetate. Hexaneof 0.7 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 8-1).

Example 17

[0123] 0.7 gram olistat was dissolved in 0.7 mL isobutyl acetate. Hexaneof 0.7 mL was added to the solution. It was dried at 20-25° C. for 24hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 9-1).

Example 18

[0124] 0.7 gram orlistat was dissolved in 0.7 mL methyl isobutyl ketone.Hexane of 0.7 mL was added to the solution. It was dried at 20-25° C.for 24 hours. It was further dried at 38° C. for 48 hours without anyfiltration (sample number 10-1).

Example 19

[0125] 0.7 gram orlistat was dissolved in 0.7 mL methanol. Hexane of 0.7mL was added to the solution. It was dried at 20-25° C. for 24 hours. Itwas further dried at 38° C. for 48 hours without any filtration (samplenumber 13-1).

Example 20

[0126] 0.7 gram orlistat was dissolved in 0.7 mL methanol. Water of 0.3mL was added to the solution. It was cooled at 0-5° C. for 1 hour.Filtered crystals were dried at 20-25° C. for 1 hour and at 38° C. for 1hour (sample number 14-1).

Example 21

[0127] 0.7 gram orlistat was dissolved in 7.0 mL hexane. Crystals werefiltered after 20 hours cooling at 0-5° C. Drying was carried out at20-25° C. for 1 hour and at 38° C. for 1 hour (sample number 16).

Example 22

[0128] The melting points (DSC) and enthapy of the following orlistatsamples were measured and presented in the following table. Thecrystalline forms (XRD) of the orlistat samples were also presented.melting enthapy Crystalline Sample endotherm ° C. (Δ) forms Numbers(DSC) (J/gram) (XRD) 1-1 46.3 87 I > II 2 47.0 92 I > II 2-1 47.1 85 I >II 3-1 46.7 87 I > II 4 46.5 91 I > II 4-1 46.8 92 I > II 5 46.2 90 I >II 5-1 46.9 90 I > II 8-1 46.9 93 I > II 9-1 46.5 85 I > II 10-1  46.588 I > II 13-1  46.7 91 I 14-1  46.2 90 I > II 16  46.6 93 II

[0129] One of ordinary skill in the art would appreciate that theexperimental conditions require optimization in order to crystallize andobtain further purified crystalline orlistat.

[0130] Pharmaceutical Formulations of Orlistat Crystalline Forms:

[0131] Orlistat crystalline forms I and II are useful for treatingobesity. They can be formulated into a variety of compositions foradministration to a mammal including humans and animals.

[0132] Pharmaceutical compositions of the present invention containorlistat crystalline form I or orlistat crystalline form II. In additionto the active ingredient(s), the pharmaceutical compositions of thepresent invention can contain one or more excipients. Excipients areadded to the composition for a variety of purposes. Diluents increasethe bulk of a solid pharmaceutical composition and can make apharmaceutical dosage form containing the composition easier for thepatient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

[0133] Solid pharmaceutical compositions that are compacted into adosage form like a tablet can include excipients whose functions includehelping to bind the active ingredient and other excipients togetherafter compression. Binders for solid pharmaceutical compositions includefor example acacia, alginic acid, carbomer (e.g. carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin,methylcellulose, polymethacrylates, povidone (e.g. Kollidon®,Plasdone®), pregelatinized starch, sodium alginate and starch.

[0134] The dissolution rate of a compacted solid pharmaceuticalcomposition in the patient's stomach can be increased by the addition ofa disintegrant to the composition. Disintegrants include for examplealginic acid, carboxymethylcellulose calcium, carboxymethylcellulosesodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide,croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®),guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.Explotab®) and starch.

[0135] Glidants can be added to improve the flowability of non-compactedsolid composition and improve the accuracy of dosing. Excipients thatcan function as glidants include for example colloidal silicon dixoide,magnesium trisilicate, powdered cellulose, starch, talc and tribasiccalcium phosphate.

[0136] When a dosage form such as a tablet is made by compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease release of theproduct form the dye. Lubricants include for example magnesium stearate,calcium stearate, glyceryl monostearate, glyceryl palmitostearate,hydrogenated castor oil, hydrogenated vegetable oil, mineral oil,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodiumstearyl fumarate, stearic acid, talc and zinc stearate.

[0137] Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include for example maltol, vanillin, ethylvanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaricacid.

[0138] Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

[0139] In liquid pharmaceutical compositions of the present invention,Orlistat crystalline form I or II, and any other solid excipients aredissolved or suspended in a liquid carrier such as water, vegetable oil,alcohol, polyethylene glycol, propylene glycol or glycerin.

[0140] Liquid pharmaceutical compositions can contain emulsifying agentsto disperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

[0141] Liquid pharmaceutical compositions of the present invention canalso contain a viscosity enhancing agent to improve the mouth-feel ofthe product and/or coat the lining of the gastrointestinal tract. Suchagents include for example acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

[0142] Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar can be added toimprove the taste.

[0143] Preservatives and chelating agents such as alcohol, sodiumbenzoate, butylated hydroxy toluene, butylated hydroxyanisole andethylenediamine tetraacetic acid can be added at levels safe foringestion to improve storage stability.

[0144] A liquid composition according to the present invention can alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate.

[0145] Selection of excipients and the amounts to use can be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

[0146] The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. The dosages can be conveniently presented in unit dosageform and prepared by any of the methods well-known in the pharmaceuticalarts.

[0147] Dosage forms include solid dosage forms like tablets, powders,capsules, suppositories, sachets, troches and losenges as well as liquidsyrups, suspensions and elixirs.

[0148] A dosage form of the present invention is a capsule containingthe composition, preferably a powdered or granulated solid compositionof the invention, within either a hard or soft shell. The shell can bemade from gelatin and optionally contain a plasticizer such as glycerinand sorbitol, and an opacifying agent or colorant.

[0149] The active ingredient and excipients can be formulated intocompositions and dosage forms according to methods known in the art.

[0150] A composition for tableting or capsule filing can be prepared bywet granulation. In wet granulation some or all of the activeingredients and excipients in powder form are blended and then furthermixed in the presence of a liquid, typically water, which causes thepowders to clump up into granules. The granulate is screened and/ormilled, dried and then screened and/or milled to the desired particlesize. The granulate can then be tableted or other excipients can beadded prior to tableting, such as a glidant and/or a lubricant.

[0151] A tableting composition can be prepared conventionally by dryblending. For instance, the blended composition of the actives andexcipients can be compacted into a slug or a sheet and then comminutedinto compacted granules. The compacted granules can be compressedsubsequently into a tablet.

[0152] As an alternative to dry granulation, a blended composition canbe compressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well-suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in particularformulation challenges of direct compression tableting.

[0153] A capsule filling of the present invention can comprise any ofthe aforementioned blends and granulates that were described withreference to tableting, only they are not subjected to a final tabletingstep.

[0154] The present invention is not to be limited in scope by thespecific embodiments described herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description andaccompanying figures. Such modifications are intended to fall within thescope of the claims. Various publications are cited herein, thedisclosure of which are incorporated by reference in their entireties.

What is claimed is:
 1. A process of preparing orlistat, comprising thesteps of hydrogenating lipstatin in an organic solvent in the presenceof a catalyst to obtain orlistat.
 2. The process of claim 1, wherein theorganic solvent is selected from the group consisting of acetonitrile,alcohol, and acetone.
 3. The process of claim 2, wherein the alcohol ismethanol.
 4. The process of claim 1, wherein the catalyst is selectedfrom the group consisting of palladium and nickel.
 5. The process ofclaim 1, wherein the hydrogenating step is performed at a temperaturebetween about 10° C. to about 50° C.
 6. The process of claim 1, whereinthe hydrogenating step is performed at pressure of less than 5 bar. 7.The process of claim 1, wherein the hydrogenating step is performed atpressure between about 1 to about 3 bar.
 8. The process of claim 1,wherein the hydrogenating step is performed at pressure of about 1 bar.9. A crystalline solid orlistat, or hydrate or solvate thereof,characterized by data selected from the group consisting of a XRDpattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta anda DSC melting endotherm at about 46.7° C. 10 The crystalline solidorlistat of claim 9, wherein the crystalline solid orlistat ischaracterized by the XRD pattern with peaks at 5.8, 18.5, 19.5 and22.3±0.2 degrees two-theta.
 11. The crystalline solid orlistat of claim10, wherein the crystalline solid orlistat is further characterized by aXRD pattern substantially as depicted in FIG.
 1. 12. The crystallinesolid orlistat of claim 9, wherein the crystalline solid orlistat ischaracterized by the DSC melting endotherm at about 46.7° C.
 13. Acrystalline solid orlistat, or hydrate or solvate thereof, characterizedby data selected from the group consisting of a XRD pattern with peaksat 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSCmelting endotherm at about 46.6° C.
 14. The crystalline solid orlistatof claim 13, wherein the crystalline solid orlistat is characterized bythe XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2degrees two-theta.
 15. The crystalline solid orlistat of claim 14,wherein the crystalline solid orlistat is further characterized by a XRDpattern substantially as depicted in FIG.
 2. 16. The crystalline solidorlistat of claim 13, wherein the crystalline solid orlistat ischaracterized by a DSC melting endotherm at about 46.6° C.
 17. A processof preparing crystalline solid orlistat, or hydrate or solvate thereof,characterized by data selected from the group consisting of a XRDpattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta anda DSC melting endotherm at about 46.7° C., comprising the steps of: (a)dissolving orlistat in a solvent; (b) adding an anti-solvent or water tothe solvent; and (c) isolating the crystalline solid orlistat.
 18. Theprocess of claim 17, wherein the solvent is a lower alkyl alcohol,acetone, acetonitrile, acetone, ethyl acetate, isobutyl acetate, methylisobutyl ketone, and hexane.
 19. The process of claim 18, wherein thelower alkyl alcohol is selected from the group consisting of methanol,ethanol, n-propanol, and isopropanol.
 20. The process of claim 17,wherein the anti-solvent is a hydrocarbon.
 21. The process of claim 20,wherein the hydrocarbon is selected from the group consisting of hexane,cyclohexane and heptane.
 22. The process of claim 17, wherein thesolvent is methanol and the anti-solvent is hexane.
 23. The process ofclaim 17, wherein the steps (a) to (c) are repeated at least once toincrease the purity of the crystalline solid orlistat.
 24. Thecrystalline solid orlistat prepared in accordance with the process ofclaim
 17. 25. The crystalline solid orlistat of claim 24, wherein thecrystalline solid orlistat is characterized by a XRD pattern with peaksat 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta.
 26. The crystallinesolid orlistat of claim 25, wherein the crystalline solid orlistat isfurther characterized by a XRD pattern substantially as depicted inFIG.
 1. 27. The crystalline solid orlistat of claim 24, wherein thecrystalline solid orlistat is characterized by a DSC melting endothermat about 46.7° C.
 28. A process for preparing a crystalline solidorlistat, or hydrate or solvate thereof, characterized by data selectedfrom the group consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9,17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSC melting endothermat about 46.6° C., comprising the steps of: (a) mixing orlistat inhexane to form a mixture at a first temperature; (b) lowering the firsttemperature of the mixture sufficiently to precipitate; and (c)isolating crystalline solid orlistat.
 29. The process of claim 28,wherein the steps (a) to (c) are repeated at least once to increase thepurity of the crystalline solid orlistat.
 30. The crystalline solidorlistat prepared in accordance with the process of claim
 28. 31. Thecrystalline solid orlistat of claim 30, wherein the crystalline solidorlistat is characterized by the XRD pattern with peaks at 4.8, 5.6,14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta.
 32. The crystallinesolid orlistat of claim 31, wherein the crystalline solid orlistat isfurther characterized by a XRD pattern substantially as depicted in FIG.2.
 33. The crystalline solid orlistat of claim 30, wherein thecrystalline solid orlistat is characterized by the DSC melting endothermat about 46.6° C.
 34. A process of preparing a mixture of crystallinesolid orlistat, or hydrate or solvate thereof, characterized by dataselected from the group consisting of a XRD pattern with peaks at 5.8,18.5, 19.5 and 22.3±0.2 degrees two-theta, a DSC melting endotherm atabout 46.7° C., a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2and 22.0±0.2 degrees two-theta, and a DSC melting endotherm at about46.6° C., comprising the steps of: (a) dissolving orlistat in a solvent;and (b) inducing crystallization to obtain the mixture of crystallinesolid orlistat.
 35. The process of claim 34, wherein the solvent is atleast one alcohol selected from the group consisting of methanol,ethanol, n-propanol, 1-propanol, 2-propanol, isopropanol, 1-butanol,i-butanol, sec-butanol, tert-butanol, N,N-dimethyl formamide, dimethylsulfoxide, acetonitrile, acetone, ethyl acetate, isobutyl acetate,methyl isobutyl ketone, and acetic acid.
 36. The process of claim 34,wherein solvent is an aliphatic hydrocarbon.
 37. The process of claim36, wherein the aliphatic hydrocarbon is selected from the groupconsisting of hexane, pentane and heptane.
 38. The process of claim 34,wherein the solvent contains water.
 39. The process of claim 34, whereinthe solvent is methanol.
 40. The process of claim 34, wherein themixture of methanol and water is present in a v/v ratio of about 1:0.3.41. The process of claim 35, wherein the solvent is a mixture of a firstalcohol in combination with a second alcohol selected from the groupconsisting of methanol, ethanol, isopropanol, propanol, butanol,sec-butanol and t-butanol.
 42. The process of claim 34, wherein thecrystallization step is induced by adding an anti-solvent.
 43. Theprocess of claim 34, wherein the crystallization step is induced bycooling.
 44. The crystalline solid orlistat as prepared by the processof one of claims 17, 28, and 34, wherein the crystalline solid orlistathas a purity of at least about 95%.
 45. The crystalline solid orlistatas prepared by the process of one of claims 17, 28 and 34, wherein thecrystalline solid orlistat has a purity of at least about 98%.
 46. Aprocess of preparing orlistat, comprising the steps of: a) preparingfermentation broth containing lipstatin; b) extracting lipstatin fromthe fermentation broth; c) hydrogenating the lipstatin to obtainorlistat; and d) separating the orlistat.
 47. The process of claim 46,wherein the hydrogenating step a) is carried out in an organic solventin the presence of a catalyst to obtain orlistat.